Recent studies have been encouraging that viral control of hepatitis C virus infection is possible. Prophylactic vaccines or efficient immunotherapies are urgently needed to reduce the disease burden of this global epidemic. HCV infects estimated 170 million people worldwide, and causes significant morbidity in developed and developing countries. Our knowledge about the mechanisms of control of viral replication and the failure to control HCV infection is still rather limited. Clearly, the outcome is determined in the early phase of the disease, therefore it seems paramount to study the earliest events that set the stage for clearance versus persistence of the virus. Various studies report an important role for both CD4+ and CD8+ in the control of viral replication. However, the majority of studies in human HCV infection utilized techniques that do not allow comprehensive and detailed assessment of the cellular immune response and were restricted to small numbers of subjects with acute infection. We propose here the analysis of the CD8+ T cell immunity in a large cohort of subjects with acute HCV infection and different transmission routes with the most precise and comprehensive techniques currently available. These studies include the analysis of the full breadth and magnitude of the CDS response on the single epitope level over the course of infection in subjects with different disease outcome, dissection of the functional and phenotypical properties of the detected specificities by the use of MHC class I tetramers and the detection of regions under selection pressure by longitudinal evolutionary data. Moreover, by utilizing an assay that allows for endogenous processing and presentation of autologous viral antigens we will be able to compare in a more physiological approach the CDS responses against the prototype HCV sequence (H77) with the response against the autologous virus. In concert with studies that address how the virus evades the activated host immune system and how they interact with the individual's CD4+ T-cell immunity this will provide important insights into the mechanisms that contribute to control and persistence of viral infection. Dissection of these mechanisms will be an important contribution to develop prophylactic vaccines or immunotherapies.